Insect repellents

ABSTRACT

A number of novel carboxamides have been found to be useful insect repellents.

This application is a division of application Ser. No. 8,814, filed Feb. 2, 1979.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to insect repellents and more particularly to certain novel carboxamides containing an alicyclic moiety and their use as insect repellents.

2. Description of the Prior Art

There is a continuing need for insect repellents or formulations thereof that are significantly more effective or longer lasting than those now in use. All of the repellents now in use for application to the skin have disadvantages, that is, they are not effective for long enough periods of time and are subject to loss by abrasion, evaporation, absorption, and immersion in water. Moreover, all cause a stinging sensation when they contact the eyelids and lips, and are effective only when they are present on the skin or clothing in relatively large quantities. Mosquitoes, sand flies, black flies, stable flies, tsetse flies, gnats, and tabanids are among the many species of biting fly that cause annoyance and distress throughout the world. Many species of biting insects spread human and animal diseases. There are many areas throughout the world in both developed and developing nations where the use of protective clothing and repellents is the only means available to individuals for personal protection. Deet (N,N-diethyl-m-toluamide) has proved to be the most outstanding all-purpose individual repellent yet developed (Proceedings of a Symposium, University of Alberta, Edmonton, Canada, May 16-18, 1972, Defense Research Board, Ottawa, Canada, 1973. DR-217: 109-113). Deet was reported as a promising repellent in 1954 (Journal of Organic Chemistry, 19, 493, 1954). Since that time, no repellent has been reported as being superior to deet as an all-purpose repellent despite a continuing search for such a chemical.

SUMMARY OF THE INVENTION

An object of this invention is to provide a class of compounds that are useful as insect repellents.

The above object is accomplished by a number of novel carboxamides having from about 11 to about 18 carbon atoms and containing an alicyclic moiety. Many of these compounds are more effective than presently available repellents and many are effective against a wide variety of insects.

DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by the formula below ##STR1## wherein R³ is one of the groups A, B, or C ##STR2## R is hydrogen or lower alkyl, n is zero or the positive integer one, two, or three, each of R¹ and R² is alkyl, or taken together represent an alkylene, an alkenylene, an alkyl substituted alkylene, an alkylene ether, and alkyl substituted alkylene ether, or an alkyl substituted alkylene amine ring structure.

The compounds of this invention are useful as insect repellents and are particularly effective against many Dipteran.

The novel compounds of this invention are especially effective in repelling a wide variety of insects such as ticks, chiggers, cockroaches, and biting diptera such as mosquitoes, stable flies, deer flies, black flies, and sand flies. Certain novel amides reported in this invention are about equally as effective as deet against mosquitoes and are significantly more repellent than deet against other biting flies when tested on skin. The skin test is the obvious critical test when one considers personal protection; however, clothing repellents are also very important especially in areas of heavy mosquito infestations (The Journal of the American Medical Association, 196, 253, 1966). Certain amides of this invention provide exceptional protection against mosquitoes when applied to cloth.

The amides were synthesized as follows: the appropriate acid chloride was slowly added with stirring to an anhydrous ether solution of the amine cooled in an ice bath (either the amine itself or pyridine was used as a hydrochloric acid scavenger). The reaction mixture was allowed to warm to room temperature and then allowed to stand for several hours, usually overnight. The amides were isolated by routine extraction procedures and purified by distillation under high vacuum. Purity was checked by gas chromatographic analysis.

A typical procedure is illustrated by the following description of the synthesis of 1-(3-cyclohexenecarbonyl) piperidine, compound 20 in Table 1: 3-cyclohexenecarbonyl chloride, 28.9 grams (0.2 mole), was added dropwise to an ice cold solution (0°-10° C.) of piperidine, 34 grams (0.4 mole) in 250 ml of anhydrous ether. The solution was stirred vigorously during the addition. The reaction mixture was allowed to warm to room temperature and to stand overnight. Water was added to dissolve the precipitated piperidine hydrochloride salt. The organic layer was then washed sequentially with 5% hydrochloric acid and sodium bicarbonate solutions and finally with a saturated salt solution until the wash was neutral to litmus paper and dried over anhydrous magnesium sulfate. After filtering, the solvent was removed under reduced pressure (water pump). The crude amide was distilled under high vacuum to give 31.4 grams of product-b.p. 114°-15° C./0.2 mm Hg), n_(D) ²⁵ 1.5159.

The physical constants of the compounds are presented in Table 1.

The repellent activity of the amides of the present invention was demonstrated by practical laboratory and field tests against mosquitoes and a variety of other biting diptera. The effectiveness of the repellents was determined by directly comparing their repellency with that of deet in tests on skin and with dimethyl phthalate in tests on cloth.

In the following description of the testing procedures the first confirmed bite is defined as a bite followed by another within thirty minutes.

For the purposes of this invention, the compounds were tested as solutes in alcohol, acetone, or other volatile solvent. However, other compatible liquid or solid carriers may also be used.

TESTING PROCEDURES Stable Flies

The repellents were applied as 1-ml aliquots of a 25% ethanol solution and spread evenly over the forearm of a subject from wrist to elbow. Since the ethanol solution was formulated on a weight-volume basis, 250 mg of repellent was applied to the forearm in each test. The most promising compounds (those equal to or better than the deet standard at the 25% dosage) were then tested as 12.5% and 6.25% ethanol solutions.

The evaluations were carried out in an outdoor cage (103 cm square and 133 cm high) constructed of aluminum and having a solid top and bottom and screen wire on four sides. Four of the sides had port openings covered with 30.5-cm (12-in.) tubular cloth stockinettes. The centers of the ports were 30 cm from the bottom of the cage, which rested on a table 80 cm high. One arm each of up to four treated subjects at a time could be inserted through the ports into the cage.

Approximately 12,000 S. calcitrans pupae were placed in cups and allowed to emerge in the test cage over an 8-day period. The tests were started the 4th day, when approximately 8000 flies had emerged. The remaining 4000 that emerged over the next 4 days maintained a relatively stable population in respect to numbers and avidity. Citrated beef blood on a cotton pad was offered for 45 minutes each day after the repellent tests were completed. This short-term feeding period provided a small but adequate food intake, and avidity was not reduced as a result of complete engorgement. Results obtained when an untreated forearm was inserted into the test cage before and during the tests each day gave a measure of the avidity of the flies, though it was impossible to count the attacks on the untreated arm.

The effectiveness of each chemical was determined by the protection time; that is, the time between treatment and the first confirmed bite. Therefore, 30 minutes after the application of the test chemical and every 30 minutes thereafter, the treated arms were inserted into the test cage for 3 minutes unless bites occurred sooner.

Since test subjects differ in attractiveness and insects differ in avidity, the best measure of the effectiveness of a repellent is its ratio of protection time vs. that of a standard repellent used in similar conditions. Deet was the standard in all of the tests reported here. It was paired with each of the other candidate repellents in 10 different test series.

The experimental design used was a round-robin series in which each repellent was paired concurrently against another repellent on the arms of a subject. An adjusted average protection time that allowed for individual variation between test subjects and test conditions was then computed (Soap and Chemical Specialties, 33, 115-17 and 129-133, 1957).

Black Flies

The principal test site was in the vicinity of Kidney Pond, Baxter State Park, Maine. Meadows bordered by fast moving mountain streams and an abundance of wildlife provided optimum breeding conditions in this area. Several species of blackflies were represented in the population attacking four test subjects. Of these, the two most abundant were identified as Simulium venustum Say and Prosimulium mixtum Syme and Davis. Repellents were applied as 1-ml aliquots of a 12.5 or 25% ethanol solution and spread evenly over the forearm of a subject from wrist to elbow. The ethanol solution was formulated on a weight-volume basis, so either 125 or 250 mg of repellent was applied in each test.

Treated arms were continuously exposed to the natural populations of flies. Subjects intermittently moved about with arms raised or on hips, squatted, or sat down for brief periods of 5 to 10 minutes. These positions, coupled with slow walking and standing every few minutes, appeared to be attractive to black flies (Simulids and Prosimulids) and were used as standard procedure in all tests. Head-nets and gloves were worn by the test subjects to prevent attack on exposed untreated parts of the body.

Two series of round-robin tests were conducted in the spring of 1977 using 12.5 or 25% solutions of repellent in ethanol; one series was conducted during June 1978 using a 25% solution of repellent in ethanol. The effectiveness of each chemical was determined by the protection time, i.e., the time between treatment and the first confirmed bite. Since test subjects differ in attractiveness and insects differ in avidity, the best measure of the effectiveness of a repellent is the ratio of its protection time to that of a standard repellent under similar conditions. Deet was the standard repellent in these tests.

In the round-robin test each repellent was paired with each other repellent on the arms of a subject (four or five replicates). An adjusted average protection time that allowed for individual variations between test subjects and test conditions was then computed. Black fly landing rates ranged from 14 to 40/minute during the test period.

Deer Flies

The compounds and the standard repellent, deet, were tested on the forearms of human subjects against natural populations of the deer fly, Chrysops atlanticus. The materials were formulated as 25% ethanol solutions and applied at the rate of 1 ml per forearm. The field tests were conducted along logging roads adjacent to the marshes of the Ogeechee River at Richmond Hill, Ga., where C. atlanticus populations occur in great numbers annually. Since the flies are attracted to motion, the test subjects continually walked while exposing their treated arms to the flies. The tests were terminated when a confirmed bite was received. The chemicals were evaluated in round-robin tests with five compounds and a deet standard in each series. During the 3-week test period the landing rate averaged 33 flies/man and ranged from 13 to 54/man.

Sand Flies

Two test sites were used, one at YankeeTown, Fla. on the Gulf coast and one at Parris Island, S.C. The repellents were applied as 25% solutions in ethanol on the forearm (wrist to elbow) of test subjects. Because of the limited period of insect activity (early morning or late afternoon to dusk) the subjects were pretreated 2 hours prior to the test period to effect aging of the repellents. The repellents were evaluated against the standard repellent, deet, in paired tests (3 replications). A test repellent was applied to one arm of a subject and deet to the other. Effectiveness was determined by the number of bites received during the test period. A control (no repellent treatment) was included in each test to ascertain the level of insect pressure.

Mosquitoes

Tests on skin--For laboratory tests, 1 ml of a 25% ethanol solution of the repellent was spread evenly over the forearm of the subject. The treated forearms were exposed to about 1500 female laboratory reared Aedes aegypti or Anopheles quadrimaculatus mosquitoes in cages. Effectiveness was based on complete protection, that is, the time between treatment and the first confirmed bite. The effectiveness of the compounds was compared to that of the standard repellent, deet. The chemicals were tested in a round-robin series in a balanced incomplete block design in which each repellent in the series was paired against each other repellent in the series on opposite arms of a given number of subjects.

The field tests were conducted at sites adjacent to Mosquito Lagoon near New Smyrna Beach, Fla. The repellents were applied in the same manner as for the laboratory tests. The treated arms were exposed continuously to the natural population of mosquitoes until the first confirmed bite was received. Protective clothing and head nets were worn by the test subjects to protect against attack on exposed untreated parts of the body. The experimental design used was a balanced incomplete block as in the laboratory tests.

Tests on cloth--Test materials were applied at the rate of 3.3 g of compound per 0.1 m² cloth to a measured portion (0.03 m³) of a cotton stocking as 10% solutions in acetone or other volatile solvent. After 2 hours, the treated stocking was placed over an untreated nylon stocking on the arm of a human subject and exposed for 1 minute in a cage containing about 1500 five- to eight-day old A. aegypti or A. quadrimaculatus. The test exposure was repeated at 24 hours and then at weekly intervals until five bites were received in 1 minute. Days to the first bite and to five bites were recorded. Between tests, the treated stockings were placed on a rack at room temperature, and evaporation was allowed to continue. A standard repellent, dimethyl phthalate, was tested concurrently and was effective for 11 to 21 days against both mosquito species.

The merits of the present invention are illustrated in the results shown in the tables.

The data in Table 2 show compounds 2, 7, 20, 33, 34, 47, and 49 were more active against the stable fly than the deet standard at all concentrations tested. Compounds 20 and 34 were significantly more effective than deet at all three dosages (0.05% level of confidence). Compounds 21 and 35 were more active than deet at two concentrations and equal to it at the lowest concentration tested. The repellent effect of certain of these chemicals was as much as 4.5×that of deet and provided protection up to 9 hours; the protection time of deet ranged from 2 to 3 hours. Data for compounds 4, 6, 17, 18, 19, 31, and 45 are shown to illustrate the unpredictability of repellent activity of closely related chemicals.

The data in Table 3 show all eight compounds and deet are very good black fly repellents. Compound 21 is significantly more effective than deet at the 25% dosage providing about 10.5 hours protection. There is no significant difference between the remaining compounds and deet at the 25% dosage. Although not significantly more effective than deet, the adjusted mean for compound 20 was 0.5 and 1.5 hours greater than that of deet at the two test dosages. Compounds 7 and 35 provided about 7 hours protection; compounds 20 and 47 provided over 8 hours protection; compounds 6 and 33 provided about 9 hours protection.

The data in Table 4 show 10 compounds that exceeded deet in repellency against deer flies. Compound 20 was significantly more effective than deet with an adjusted mean protection time of 6.3 hours.

The data in Table 5 show compounds 2, 7, 20, and 35 greatly superior to deet in tests conducted in Florida against the sand fly Culicoides mississippiensis. Compounds 2 and 20 were also superior to deet in the Parris Island tests against Culicoides hollensis. Deet is considered a good repellent for sand flies (Meditsinskaya Parazitologiya i Parazitarnye Bolezni, 35 (5), 549, 1963). A biting rate of about 5/hour would make the presence of sand flies tolerable to most people (Journal of Economic Entomology, 64 (1), 264, 1971). The data show certain compounds of this invention equalling or exceeding this criteria in one test and equalling or closely approaching it in the second test. The number of bites experienced by the check, clearly shows very high insect pressure during these tests, emphasizing the effectiveness of the repellents.

The data in Table 6 show the relative repellency of compounds of this invention against mosquitoes when applied to skin in laboratory and field tests. Deet is an excellent mosquito repellent (The Journal of the American Medical Association, 196, 253, 1966). Repellents 33 and 34 were about equally as effective against Aedes aegypti as deet; repellents 19, 20, 21, and 34 were about equally as effective against Anopheles quadrimaculatus as deet. In field tests, repellents 2 and 20 were 1.5 and 1.4 times as effective as deet against Aedes taeniorhynchus and 4, 6, 7, 21, 33, and 47 were about equally as effective as deet. Because deet is such an effective mosquito repellent, chemicals having 0.5 ratios to deet are considered good mosquito repellents.

The data in Table 7 show 91 of the repellents were more effective than the standard against one species of mosquito and 9 other compounds were about equally as effective as the standard. Repellents 91, 100, 101, and 115 provided outstanding protection of over 200 days and 29 other repellents provided exceptional protection of over 100 days against one species or the other. All chemicals providing 11 or more days protection are considered promising repellents.

The foregoing examples of repellent action of these novel amides against specific insect pests is meant to be illustrative rather than limiting. For example, the compounds of the present invention can be mixed with inert ingredients or with other known insect repellents. The compounds may also be formulated or embodied into repellent compositions in the form of creams, lotions, emulsions, suspensions, solutions, dusts, and aerosol or other type of sprays.

Although inert repellents are usually applied to the skin, the compounds of this invention and formulations containing them are also useful when applied to clothing, netting, packaging, shipping containers, animals, and growing plants.

                                      TABLE 1                                      __________________________________________________________________________     Physical constants of compounds synthesized in accordance with the             procedures of this invention                                                    No.                                                                                ##STR3##      Physical constants B.p. (°C./mm Hg) or m.p.                            (°C.)                                                                             n.sub.D.sup.25                                                                     No.                                                                                 ##STR4##      Physical constants                                                            B.p. (°C./mm Hg)                                                        r m.p.                                                                                   n.sub.D.sup.25     __________________________________________________________________________      ##STR5##                                                                      1   N,N-Dimethylamino                                                                            69-70/0.45                                                                              1.4794                                                                             9    4-Methyl-1-piperidyl                                                                         113-14/0.8                                                                              1.4970              2   N,N-Dipropylamino                                                                            93-5/0.45                                                                               1.4685                                                                             10   2-Ethyl-1-piperidyl                                                                          131/1.5  1.4970              3   N,N-Dibutylamino                                                                             133/1.5  1.4675                                                                             11   2,6-Dimethyl-1-piperidyl                                                                     109-11/0.5                                                                              1.4950              4   1-Pyrrolidyl  67-8         12   1,2,3,6-Tetrahydro-1-                                                          pyridinyl     107-9/0.5                                                                               1.5175              5   1-Piperidyl   108/0.45 1.5030                                                                             13   4-Methyl-1-piperazinyl                                                                       100-2/0.1                                                                               1.5041              6   1-Hexahydro-1H-azepinyl                                                                      120/0.25 1.5038                                                                             14   4-Morpholinyl 57-8                         7   2-Methyl-1-piperidyl                                                                         110-13/0.7                                                                              1.5001                                                                             15   2,6-Dimethyl-4-morpholinyl                                                                   116-17/0.3                                                                              1.4919              8   3-Methyl-1-piperidyl                                                                         114-16/0.45                                                                             1.4974                                              __________________________________________________________________________      ##STR6##                                                                      16  N,N-Dimethylamino                                                                            75-6/0.4 1.4960                                                                             24   4-Methyl-1-piperidyl                                                                         110-12/0.15                                                                             1.5087              17  N,N-Dipropylamino                                                                            88/0.15  1.4804                                                                             25   2-Ethyl-1-piperidyl                                                                          114-15/0.1                                                                              1.5068              18  N,N-Dibutylamino                                                                             103/0.1  1.4775                                                                             26   2,6-Dimethyl-1-piperidyl                                                                     112-13/0.1                                                                              1.5055              19  1-Pyrrolidyl  44-5         27   1,2,3,6-Tetrahydro-1-                                                          pyridinyl     114-16/0.45                                                                             1.5315              20  1-Piperidyl   114-15/0.2                                                                              1.5159                                                                             28   4-Methyl-1-piperazinyl                                                                       112-14/0.1                                                                              1.5181              21  1-Hexahydro-1H-azepinyl                                                                      105-6/0.15                                                                              1.5151                                                                             29   4-Morpholinyl 114-16/0.25                                                                             1.5194              22  2-Methyl-1-piperidyl                                                                         110-12/0.1                                                                              1.5106                                                                             30   2,6-Dimethyl-4-morpholinyl                                                                   115-16/0.4                                                                              1.5043              23  3-Methyl-1-piperidyl                                                                         108-10/0.1                                                                              1.5087                                              __________________________________________________________________________      ##STR7##                                                                      31  N,N-Dipropylamino                                                                            100/0.7  1.4682                                                                             38   4-Methyl-1-piperidyl                                                                         108/0.8  1.4908              32  N,N-Dibutylamino                                                                             126/0.9  1.4669                                                                             39   2-Ethyl-1-piperidyl                                                                          175-8/18 1.4930              33  1-Pyrrolidyl  95/0.25  1.4941                                                                             40   2,6-Dimethyl-1-piperidyl                                                                     108-10/0.5                                                                              1.4905              34  1-Piperidyl   104-6/0.5                                                                               1.4970                                                                             41   1,2,3,6-Tetrahydro-1-                                                          pyridinyl     118-20/1.3                                                                              1.5100              35  1-Hexahydro-1H-azepinyl                                                                      115-18/0.9                                                                              1.5000                                                                             42   4-Methyl-1-piperazinyl                                                                       120-2/1.0                                                                               1.4990              36  2-Methyl-1-piperidyl                                                                         141-3/0.25                                                                              1.4930                                                                             43   4-Morpholinyl 108-9/0.4                                                                               1.4975              37  3-Methyl-1-piperidyl                                                                         168-70/18                                                                               1.4909                                                                             44   2,6-Dimethyl-4-morpholinyl                                                                   75-7                         __________________________________________________________________________      ##STR8##                                                                      45   N,N-Dipropylamino                                                                           108/2.0  1.4794                                                                             52   4-Methyl-1-piperidyl                                                                         122-4/1.0                                                                               1.5020              46  N,N-Dibutylamino                                                                             120/0.45 1.4765                                                                             53   2-Ethyl-1-piperidyl                                                                          116-18/0.5                                                                              1.5036              47  1-Pyrrolidyl  133-6/0.2                                                                               1.5082                                                                             54   2,6-Dimethyl-1-piperidyl                                                                     115-17/0.5                                                                              1.5017              48  1-Piperidyl   109/0.5  1.5090                                                                             55   1,2,3,6-Tetrahydro-1-                                                          pyridinyl     113-15/0.7                                                                              1.5234              49  1-Hexahydro-1H-azepinyl                                                                      135/0.9  1.5116                                                                             56   4-Methyl-1-piperazinyl                                                                       105-7/0.3                                                                               1.5106              50  2-Methyl-1-piperidyl                                                                         120-2/1.1                                                                               1.5049                                                                             57   4-Morpholinyl 104-5/0.2                                                                               1.5115              51  3-Methyl-1-piperidyl                                                                         120-2/1.3                                                                               1.5035                                                                             58   2,6-Dimethyl-4-morpholinyl                                                                   122-5/0.4                                                                               1.4990              __________________________________________________________________________      ##STR9##                                                                      59  N,N-Dipropylamino                                                                            93-5/0.2 1.4900                                                                             66   4-Methyl-1-piperidyl                                                                         98-100/0.1                                                                              1.5163              60  N,N-Dibutylamino                                                                             100-2/0.1                                                                               1.4862                                                                             67   2-Ethyl-1-piperidyl                                                                          108-9/0.15                                                                              1.5168              61  1-Pyrrolidyl  105-8/0.15                                                                              1.5262                                                                             68   2,6-Dimethyl-1-piperidyl                                                                     100-1/0.15                                                                              1.5166              62  1-Piperidyl   111-13/0.2                                                                              1.5244                                                                             69   1,2,3,6-Tetrahydro-1-                                                          pyridinyl     110/0.1  1.5401              63  1-Hexahydro-1H-azepinyl                                                                      121-2/0.4                                                                               1.5262                                                                             70   4-Methyl-1-piperazinyl                                                                       103-4/0.1                                                                               1.5253              64  2-Methyl-1-piperidyl                                                                         108-9/0.2                                                                               1.5197                                                                             71   4-Morpholinyl 99-100/0.1                                                                              1.5258              65  3-Methyl-1-piperidyl                                                                         110-12/0.3                                                                              1.5169                                                                             72   2,6-Dimethyl-4-morpholinyl                                                                   100-2/0.1                                                                               1.5113              __________________________________________________________________________      ##STR10##                                                                     73  N,N-Dimethylamino                                                                            87-8/0.45                                                                               1.4780                                                                             81   4-Methyl-1-piperidyl                                                                         121/0.5  1.4935              74  N,N-Dipropylamino                                                                            108-9/0.45                                                                              1.4708                                                                             82   2-Ethyl-1-piperidyl                                                                          122-4/0.2                                                                               1.4943              75  N,N-Dibutylamino                                                                             139/0.75 1.4698                                                                             83   2,6-Dimethyl-1-piperidyl                                                                     121-3/0.3                                                                               1.4942              76  1-Pyrrolidyl  110-12/0.25                                                                             1.4977                                                                             84   1,2,3,6-Tetrahydro-1-                                                          pyridinyl     122-4/0.15                                                                              1.5114              77  1-Piperidyl   109-11/0.2                                                                              1.5000                                                                             85   4-Methyl-1-piperazinyl                                                                       109/0.15 1.5016              78  1-Hexahydro-1H-azepinyl                                                                      114-16/0.2                                                                              1.5019                                                                             86   4-Morpholinyl 68-70                        79  2-Methyl-1-piperidyl                                                                         105-7/0.2                                                                               1.4945                                                                             87   2,6-Dimethyl-4-morpholinyl                                                                   125-7/0.5                                                                               1.4892              80  3-Methyl-1-piperidyl                                                                         118/0.4  1.4942                                              __________________________________________________________________________      ##STR11##                                                                     88  N,N-Dimethylamino                                                                            100-2/0.4                                                                               1.4782                                                                             96   4-Methyl-1-piperidyl                                                                         136-7/0.5                                                                               1.4919              89  N,N-Dipropylamino                                                                            117-18/0.45                                                                             1.4715                                                                             97   2-Ethyl-1-piperidyl                                                                          126-7/0.1                                                                               1.4938              90  N,N-Dibutylamino                                                                             133-5/0.4                                                                               1.4701                                                                             98   2,6-Dimethyl-1-piperidyl                                                                     135/0.35 1.4895              91  1-Pyrrolidyl  126-7/0.2                                                                               1.4928                                                                             99   1,2,3,6-Tetrahydro-1-                                                          pyridinyl     134-5/0.5                                                                               1.5070              92  1-Piperidyl   129-31/0.2                                                                              1.4950                                                                             100  4-Methyl-1-piperazinyl                                                                       139-40/0.1                                                                              1.4966              93  1-Hexahydro-1H-azepinyl                                                                      131-4/0.3                                                                               1.4985                                                                             101  4-Morpholinyl 122-4/0.1                                                                               1.4961              94  2-Methyl-1-piperidyl                                                                         128-30/0.35                                                                             1.4933                                                                             102  2,6-Dimethyl-4-morpholinyl                                                                   123-5/0.1                                                                               1.4876              95  3-Methyl-1-piperidyl                                                                         136-8/0.5                                                                               1.4912                                              __________________________________________________________________________      ##STR12##                                                                     103 N,N-Dimethylamino                                                                            109-10/0.4                                                                              1.4764                                                                             111  4-Methyl-1-piperidyl                                                                         145-7/0.45                                                                              1.4875              104 N,N-Dipropylamino                                                                            128-30/0.4                                                                              1.4712                                                                             112  2-Ethyl-1-piperidyl                                                                          145/0.25 1.4910              105 N,N-Dibutylamino                                                                             148/0.4  1.4705                                                                             113  2,6-Dimethyl-1-piperidyl                                                                     151-3/0.5                                                                               1.4874              106 1-Pyrrolidyl  137-9/0.4                                                                               1.4905                                                                             114  1,2,3,6-Tetrahydro-1-                                                          pyridinyl     145-6/0.45                                                                              1.5035              107 1-Piperidyl   139-40/0.5                                                                              1.4920                                                                             115  4-Methyl-1-piperazinyl                                                                       134-5/0.15                                                                              1.4975              108 1-Hexahydro-1H-azepinyl                                                                      153-4/0.5                                                                               1.4940                                                                             116  4-Morpholinyl 149-51/0.45                                                                             1.4932              109 2-Methyl-1-piperidyl                                                                         142-3/0.45                                                                              1.4909                                                                             117  2,6-Dimethyl-4-morpholinyl                                                                   145-7/0.45                                                                              1.4828              110 3-Methyl-1-piperidyl                                                                         143-5/0.5                                                                               1.4882                                              __________________________________________________________________________

                  TABLE                                                            ______________________________________                                         Repellency of compounds to the stable fly Stomoxyx                             calcitrans when applied to the skin at various concentrations                  in ethanol and compared to deet as a test standard                                      Protection time                                                                (minutes)                                                                   %                  Adjusted                                                                              Ratio to                                                                               No. of                                 No.   Conc.    Range     mean   deet.sup.a                                                                             tests                                  ______________________________________                                         2     6.25     30-90     55     1.7     3                                            12.5     300-360   315    4.50.sup.b                                                                             5                                            25.0     210-463   321    2.02.sup.b                                                                             5                                      4     25.0     30-270    103    0.4     5                                      6     25.0     30-268    183    0.71    5                                      7     25.0     120-300   246    2.01.sup.b                                                                             4                                      17    25.0     180-360   225    0.85    5                                      18    25.0     30-189    122    0.46    5                                      19    25.0     90-420    237    1.0     5                                      20    6.25     30-120    103    2.5.sup.b                                                                              3                                            12.5     60-240    128    2.4.sup.b                                                                              4                                            25.0     360-390   387    2.39.sup.b                                                                             5                                      21    6.25     30-60     33     1.0     5                                            12.5     270-450   306    1.42    5                                            25.0     300-510   457    3.78.sup.b                                                                             4                                      31    25.0     30-60     36     0.2     5                                      33    6.25     60-180    80     1.6     3                                            12.5     90- 210   150    3.3.sup.b                                                                              4                                            25.0     240-270   266    1.6     4                                      34    6.25     30-120    118    2.4.sup.b                                                                              3                                            12.5     270-330   320    4.57.sup.b                                                                             5                                            25.0     390-510   419    2.6.sup.b                                                                              4                                      35    6.25     30--30    30     1.0     5                                            12.5     210-375   326    3.27.sup.b                                                                             5                                            25.0     390-510   459    2.9.sup.b                                                                              4                                      36    25.0     30-120    101    1.43    5                                      45    25.0     30-180    78     0.44    5                                      47    6.25     30-90     63     1.9     3                                            12.5     120-270   230    3.29.sup.b                                                                             5                                            25.0     150-405   264    1.66    5                                      49    6.25     30-60     38     1.15    5                                            12.5     150-330   306    1.42    5                                            25.0     480-510   538    3.02.sup.b                                                                             5                                      50    25.0     60-150    125    1.41    5                                      ______________________________________                                          .sup.a Data compiled from a number of different tests, accounting for the      fluctuation between protection time and ratio to deet among the members o      the series.                                                                    .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 3                                                          ______________________________________                                         Repellency of compounds applied to the skin as 12.5 and/or                     25% ethanol solutions compared with deet against                               blackflies in two series of field tests                                                 Protection time (min)                                                         %                         Ratio to                                                                              No. of                                No.     Conc.  Range    Adjusted mean                                                                            deet   tests                                 ______________________________________                                         Test I (1977)                                                                  Deet (Std)                                                                             12.5   145-283  161       1.00   5                                             25.0   287-511  426       1.00   4                                     20      12.5   123-314  193       1.20.sup.a                                                                            5 - 25.0 413-565 505 1.19.sup.a 4                                              2                                     7       12.5    26-222   95       0.59   5                                             25.0   309-515  424       1.00.sup.a                                                                            4                                     35      12.5    24-126   93       0.58   5                                             25.0   342-542  412       0.97.sup.a                                                                            4                                     2       12.5    25-112   71       0.44   5                                             25.0   198-375  314       0.74.sup.a                                                                            4                                     Test II (1978)                                                                 Deet (Std)                                                                             25.0   399-623  520       1.00   5                                     6       25.0   411-628  537       1.03.sup.a                                                                            5                                     21      25.0   524-725  632       1.21.sup.b                                                                            5                                     33      25.0   498-603  554       1.07.sup.a                                                                            5                                     47      25.0   425-649  486       0.94.sup.a                                                                            5                                     ______________________________________                                          .sup.a Not significantly different from deet at the 0.05% level of             confidence.                                                                    .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 4                                                          ______________________________________                                         Repellency of compounds applied to the skins as                                25% ethanol solutions and compared with deet against                           deerflies in field tests (Avg. of 5 tests)                                            Protection time (min)                                                                                     Ratio to                                     No.      Range    Adjusted mean   deet.sup.a                                   ______________________________________                                         2        10-178   133             3.00                                         4        4-77     23              0.51                                         6        10-173   75              1.69                                         17       15-143   62              1.39                                         18       6-36     40              0.89                                         20       363-421  380             5.83.sup.b                                   21       91-203   91              1.1                                          31       10-44    45              0.62                                         34       20-408   141             1.8                                          35       42-182   119             1.5                                          36       5-17     15              0.94                                         45       4-110    18              0.24                                         47       40-160   138             1.89                                         49       37-244   129             1.76                                         50       8-138    27              1.11                                         ______________________________________                                          .sup.a Data compiled from a number of tests, accounting for the                fluctuation between the protection time and ratio to deet among the            members of the series.                                                         .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 5                                                          ______________________________________                                         Repellency of compounds applied to the skin                                    as 25% ethanol solutions and compared with deet                                against the sandflies Culicoides mississippiensis                              and Culicoides hollensis in field tests                                        Compounds      Average  Average                                                paired         bites/test                                                                              bites/hour                                             ______________________________________                                         Tests at Yankee Town, Fla. (Avg. 3 tests)                                      Deet           29.0     19.2                                                   2              3.33     2.4                                                    Deet           31.67    21.0                                                   20             5.0      3.6                                                    Deet           106.0    70.8                                                   35             6.67     4.2                                                    Deet           45.0     30.0                                                   7              10.0     6.6                                                    Check          1299     865.8                                                  ______________________________________                                         Tests at Parris Island, S.C. (Avg. 3 tests)                                    Deet           28.67    18.6                                                   20             9.33     6.0                                                    Deet           85.0     54.6                                                   2              16.33    10.8                                                   Deet           12.0     7.8                                                    7              16.67    10.8                                                   Check          1566     1277.4                                                 ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                         Repellency of compounds to mosquitoes when applied                             to the skin as 25% ethanol solutions                                                  Ratio to deet                                                                  Laboratory test                                                                               Field test                                                        Aedes   Anopheles   Aedes                                             No.      aegypti quadrimaculatus                                                                            taeniorhynchus                                    ______________________________________                                         2        0.22    0.28        1.5                                               4        0.22    0.11        0.77                                              6        0.14    0.74        0.82                                              7        0.70    0.11        1.15                                              17       0.24    0.33        0.52                                              18       0.13    0.05        0.07                                              19       0.20    0.73        0.44                                              20       0.68    1.0         1.4                                               21       0.64    0.86        0.7                                               31       0.24    0.08        0.45                                              33       1.12    0.86        0.69                                              34       0.89    1.0         0.34                                              45       0.23    0.11        0.12                                              47       0.28    0.24        0.99                                              49       0.55    0.09        0.65                                              ______________________________________                                    

                  TABLE 7                                                          ______________________________________                                         Repellency of compounds to mosquitoes in tests on cloth                                Aedes aegypti                                                                              Anopheles quadrimaculatus                                         Days to     Days to                                                     No.      1st bite                                                                               5 bites   1st bite                                                                               5 bites                                     ______________________________________                                         2        15      15        8       8                                           4        30      38        38      79                                          5        30      38        30      30                                          6        106     113       22      38                                          7        104     104       111     111                                         8        104     104       22      22                                          9        52      104       0       22                                          10       104     104       1       22                                          11       104     104       1       37                                          12       15      15        15      15                                          13       7       15        7       111                                         14       0       1         27      27                                          15       15      28        35      35                                          17       15      15        15      15                                          18       0       30        0       1                                           19       28      28        70      94                                          20       21      28        28      48                                          21       64      87        70      70                                          22       69      69        83      83                                          23       36      36        36      51                                          24       20      20        83      83                                          25       83      83        83      83                                          26       36      36        36      36                                          27       36      36        63      63                                          28       28      28        63      83                                          29       0       0         35      35                                          30       8       8         22      22                                          31       15      15        1       1                                           33       21      28        28      28                                          34       21      28        13      13                                          35       28      28        6       6                                           36       23      43        0       0                                           37       23      51        0       0                                           38       36      36        21      21                                          39       51      71        0       0                                           40       1       23        0       0                                           41       8       15        8       8                                           42       1       1         36      50                                          43       36      77        64      71                                          44       28      28        15      15                                          45       27      27        1       1                                           47       27      27        1       1                                           48       33      41        1       1                                           49       27      47        1       1                                           50       23      51        0       23                                          51       36      36        0       21                                          52       36      36        8       36                                          55       15      15        0       1                                           57       8       22        36      105                                         58       1       28        22      22                                          59       1       35        49      49                                          61       34      55        28      28                                          62       70      70        70      91                                          63       70      128       0       111                                         64       70      70        0       76                                          65       35      70        0       49                                          66       70      70        0       77                                          67       21      34        47      47                                          68       1       28        20      20                                          69       28      28        20      20                                          70       28      28        47      47                                          71       0       0         47      47                                          72       0       34        20      190                                         74       0       0         28      28                                          76       108     108       21      119                                         77       28      108       28      28                                          78       21      130       1       8                                           79       28      102       0       0                                           80       28      102       0       0                                           81       28      51        8       8                                           82       0       28        8       8                                           83       101     108       108     108                                         84       8       28        28      28                                          85       0       105       134     175                                         86       0       1         1       18                                          87       0       105       126     126                                         88       21      21        24      24                                          91       169     169       238     238                                         92       29      29        7       182                                         93       21      65        21      44                                          94       7       21        1       1                                           95       7       21        1       126                                         97       0       12        0       12                                          98       0       21        126     126                                         99       0       12        0       93                                          100      7       7         21      268                                         101      61      133       238     238                                         102      61      93        133     133                                         103      42      42        24      54                                          106      61      160       160     160                                         107      0       36        36      36                                          108      22      22        36      134                                         110      0       1         36      36                                          111      0       0         52      94                                          112      13      13        36      104                                         113      0       1         134     134                                         114      0       36        134     134                                         115      0       51        310     318+                                        116      77      134       134     134                                         117      22      22        134     134                                         ______________________________________                                          +Compound still in test.                                                  

We claim:
 1. A method of repelling stable flies, black flies, deer flies, sand flies, and mosquitoes comprising applying to the skin or to clothing an effective insect repellent amount of a compound of the formula ##STR13## wherein R³ is one of the groups A, B, or C ##STR14## R is hydrogen or lower alkyl, and n is the positive integer one, two, or three and R¹ and R² taken together with the N is selected from the group consisting of ##STR15## wherein when x is methyl, y and z are hydrogen, and p is either methyl or hydrogen; when y is methyl, x, z, and p are hydrogen; when z is methyl, x, y, and p are hydrogen; and when x is ethyl, y, z, and p are hydrogen.
 2. The method according to claim 1 wherein the compound is applied to the skin.
 3. The method according to claim 1 wherein the compound is applied to cloth.
 4. The method of claim 1 wherein the compound R³ is ##STR16##
 5. The method of claim 4 wherein R¹ and R² taken together with the N is selected from the group consisting of 2-methyl-1-piperidyl; 3-methyl-1-piperidyl; 4-methyl-1-piperidyl; 2-ethyl-1-piperidyl; 2,6-dimethyl-1-piperidyl; and 1-piperidyl.
 6. The method of claim 1 wherein in the compound R³ is ##STR17##
 7. The method of claim 6 wherein R¹ and R² taken together with the N is selected from the group consisting of 1-piperidyl; and 2-methyl-1-piperidyl.
 8. The method of claim 1 wherein in the compound R³ is ##STR18##
 9. The method of claim 8 wherein R¹ and R² taken together with the N is 1-piperidyl. 